91 research outputs found
Les cyclopropanes monofluorés (nouvelle architecture pour la conception de peptidomimétiques)
L intĂ©rĂȘt des composĂ©s organiques fluorĂ©s est de nos jours de plus en plus important en raison de leur large domaine d application (agrochimie, nuclĂ©aire, matĂ©riaux, chimie mĂ©dicinale ). Par exemple, en chimie mĂ©dicinale, la prĂ©sence d un ou plusieurs atomes de fluor au sein de biomolĂ©cules conduit trĂšs souvent Ă une amĂ©lioration de leur profil thĂ©rapeutique. Par ailleurs, le cyclopropane, le plus petit et le plus tendu des cycloalcanes, permet Ă©galement de modifier les caractĂ©ristiques pharmacologiques de composĂ©s biologiques de par sa gĂ©omĂ©trie inhabituelle. En effet, la rigidification structurale apportĂ©e par ce motif influe sur la biodisponibilitĂ© d une biomolĂ©cule en amĂ©liorant sa sĂ©lectivitĂ© et son affinitĂ© pour un rĂ©cepteur biologique. Dans ce contexte, nous avons choisi d associer les propriĂ©tĂ©s remarquables de l atome de fluor Ă la contrainte structurale du cyclopropane dans le but d Ă©laborer deux nouvelles classes de fluoropeptidomimĂ©tiques.Tout d abord, nous nous sommes intĂ©ressĂ©s Ă la modification de la chaĂźne latĂ©rale d acides aminĂ©s naturels en dĂ©veloppant la synthĂšse des analogues cyclopropaniques fluorĂ©s de la mĂ©thionine, de la leucine, de la lysine et de l arginine. Nous avons ensuite appliquĂ© l un de nos acides aminĂ©s cyclopropaniques fluorĂ©s Ă la synthĂšse totale de l analogue fluorĂ© d un inhibiteur de la sĂ©rineprotĂ©ase NS3/4A, le TMC 435.Enfin, dans le but de proposer une voie de synthĂšse gĂ©nĂ©rale permettant l accĂšs aux pseudopeptides fluorĂ©s comportant un monofluorocyclopropane Ă la place du lien peptidique, nous avons dĂ©veloppĂ© une nouvelle stratĂ©gie basĂ©e sur une Ă©tape d addition nuclĂ©ophile de rĂ©actifs organomĂ©talliques sur des N-(tert-butanesulfinyl)-a-fluoroimines chirales.Fluoroorganic compounds are increasingly popular owing to their wide range of applications. For instance, in the field of medicinal chemistry, fluorinated molecules often lead to an improvement of the therapeutic profile compared to non-fluorinated derivatives. Besides, with its unique bonding properties, the cyclopropane ring provides unusual physical and pharmacological properties to structures that incorporate it. Indeed, the structural constraint provided by the cyclopropane ring clearly alters the selectivity and the affinity for a binding site. In this context, we decided to combine the cyclopropane and the fluorine atom to develop two new classes of peptidomimetics. First, we focused on the modification of the side chain of natural aminoacids (methionine, leucine,lysine and arginine) and the synthesis of fluorinated cyclopropyl analogues was achieved. Then, we applied our strategy to the synthesis of the fluorinated analogue of the TMC 435, a NS3/4A serine protease inhibitor involved in the replication cycle of Hepatitis C virus. Finally, in our project aiming at proposing a general method to access pseudopeptides featuring a fluorinated cyclopropane moiety as the peptide bond isostere, we develop a new strategy based on the nucleophilic addition of organometallic reagents to N-(tert-butanesulfinyl)-a-fluoroimines. This methodology allows us to control the asymmetric center on the N-terminal side of the peptide.ROUEN-INSA Madrillet (765752301) / SudocSudocFranceF
Access to Isothiazolones from Simple Acrylamides by Pd-Catalyzed CâH Bond Activation
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Nouveaux ligands mixtes de type phosphore / carbÚne N-hétérocyclique (synthÚse et applications en catalyse asymétrique)
Une méthode simple et efficace a été développée pour la préparation de ligands bifonctionnels associant les motifs phosphine ou phosphite d'une part, et carbÚne Nhétérocyclique(NHC) ou imidazolium d'autre part. Dans un premier temps, une série de ligands diphénylphosphine-carbÚne chiraux portant un centre stéréogÚne en a de la phosphinea été développée à partir b-hydroxyesters. Une famille de ligands a ainsi été développée afin d'évaluer l'influence de l'encombrement stérique de différents groupements alkyles en a de la phosphine et de la nature des groupements aromatiques portés sur l'imidazole sur leur activité catalytique. L étude s est ensuite étendue à la synthÚse de ligands de type dialkylphosphine carbÚne et phosphite-carbÚne. Ces différents ligands ont été complexés avec des métaux tels que l iridium ou le rhodium de maniÚre à en étudier l activité en hydrogénation asymétrique.A straightforward method for the preparation of new bidentate ligands containing aphosphine or a phosphite and a carbene function was developed. Different phosphorus-imidazolium compounds were prepared according to this method. First, diphenylphosphine-NHC ligands featuring a stereogenic center a to the phosphine were synthesized from b-hydroxyesters. This strategy was then extended to the preparation of phosphite-imidazoliumand dialkylphosphine-imidazolium compounds. Complexation of these phosphorus-NHCligands with different metals like Ir or Rh was performed in order to study there catalytic properties in asymmetric hydrogenation.ROUEN-INSA Madrillet (765752301) / SudocSudocFranceF
SynthÚse des cyclopropylcarboxylates fluorés originaux
Les composĂ©s organofluorĂ©s constituent une grande partie de produits pharmaceutiques, ainsi que pesticides, herbicides et matĂ©riaux fabriquĂ©s actuellement. DĂ©veloppement des mĂ©thodes sĂ©lectives de la synthĂšse des composĂ©s organofluorĂ©s est donc d'intĂ©rĂȘt principal pour la chimie. Dans cette thĂšse, nous dĂ©crivons la nouvelle mĂ©thode de synthĂšse des cyclopropanes monofluorĂ©s basĂ© sur la cyclisation initiĂ©e par la rĂ©action de MichaĂ«l (MIRC). Notre mĂ©thode permet d'obtenir les cyclopropanes monofluorĂ©s polysubstituĂ©s Ă partir de dibromofluorocetate d'Ă©thyle et diffĂ©rents accpteurs de MichaĂ«l. Nous avons aussi rĂ©alisĂ© la cyclopropanation asymĂ©trique en utilisant le nouveau rĂ©actif fluorĂ© chiral Ă base d'oxazolidinone. Dans la partie finale de cette thĂšse nous dĂ©crivons la synthĂšse de l'analogue fluorĂ© de L-FAP4, l'agoniste puissant des rĂ©cepteurs mĂ©tabotropiques de glutamate groupe II(mGluR II), afin d'augmenter l'activitĂ© biologique et la biodisponibilitĂ© de ce composĂ©.Organofluorine compounds constitute a large part of all the drugs, crop protection agents and advanced materials produced nowadays. Therefore, there is a great interest in developing the new methods of synthesis of organofluorine compounds. In this thesis we report a novel method of synthesis of monofluorinated cyclopropanes based on the Michael-initiating ring closure (MIRC) reaction. Our method allows obtaining polysubstituted monofluorinated cyclopropanes from ethyl dibromofluoroacetate and various Michael acceptors. We have also implemented the asymetric version of cyclopropanation using a novel oxazolodinone-derived chiral fluorinated reagent. In the final part of this thesis we report the synthesis of a fluorinated analog of L-FAP4, a potent agonist of group II metabotropic glutamate receptors (mGluR II). Incorporation of a fluorine atom is expected to increase the biological activity and bioavailabiblity of this compound.ROUEN-INSA Madrillet (765752301) / SudocSudocFranceF
Ru(II)âCatalyzed Hydroarylation of in situ generated 3,3,3âTrifluoroâ1âpropyne by CâH Bond Activation: A Facile and Practical Access to ÎČâtrifluoromethylstyrenes
International audienceIn this study, a practical and straightforward synthesis of ÎČ-( E )-trifluoromethylstyrenes by ruthenium-catalyzed C-H bond activation was developed. The readily available and inexpensive 2-bromo-3,3,3-trifluoropropene (BTP), a non-ozone depleting reagent, was used as a reservoir of 3,3,3-trifluoropropyne. With this approach, the monofunctionalization of a panel of heteroarenes was possible in a safe and scalable manner (23 examples, up to 87% yield). Mechanistic investigations and density functional theory (DFT) calculations were also conducted to get a better understanding of the mechanism of this transformation. These studies suggested that 1) a cyclometallated ruthenium complex enabled the transformation, 2) this latter exhibited high efficiency in this transformation compared to the commercially available [RuCl 2 ( p -cymene)] 2 and 3) the mechanism proceeded through a bis-cyclometallated ruthenium intermediate for the carboruthenation ste
Stereoselective Access to ÎČ-C-Glycosamines by Nitro-Michael Addition of Organolithium Reagents
International audienceThe nitro-Michael addition of organolithium species to 2 nitroglycal derivatives was investigated. This methodology affords straightforward and stereoselective access to C-nitroglycosides, which are excellent precursors to CâN-acetyl-glycosamines. The corresponding products bearing an aromatic, heteroaromatic, alkynyl, alkenyl, or alkyl moiety were isolated in good yields with excellent selectivities. The ÎČ isomer was isolated as a single stereoisomer in most cases, and the structure was clearly elucidated by NMR spectroscopy experiments
New entries toward the synthesis of OCF3-containing molecules
International audienceThe OCF3 group is of high interest in the quest for new drugs and agrochemicals, thanks to its atypical features. This Highlight article depicts the recent and impressive advances toward the synthesis of OCF3-containing molecule
Recent advances in photocatalyzed reactions using well-defined copper(I) complexes
International audienceThis review summarizes the recent advances in photocatalysis using copper complexes. Their applications in various reactions, such as ATRA, reduction, oxidation, proton-coupled electron transfer, and energy transfer reactions are discussed
Slats façades / Fachadas en CelosĂa
COSTE, Anne, MESTRE, Octavio, MAURETTE, Carlos, et al., 2013. Slats façades / Fachadas en CelosĂa. Barcelone : Monsa, 2013. 221 p. ISBN 978-84-15829-23-2. The Venetian blind pays homage to the shade, as a subtle mechanism capable of showcasing the light. Because, all in all, light is all we have left. We architects build spaces for the light to inhabit. Is an element of climate control that provides thermal inertia to the façade. The recent curtain walls, inside which access can be made for m..
A multi-step continuous flow synthesis of pomalidomide
International audienceThe immunomodulatory drugs (IMiDs) thalidomide, pomalidomide, and lenalidomide are widely used to treat multiple myeloma. The permanent need of IMiDs analogues in clinical screening and practice has created the demand to find a reliable and robust method for their preparation. To reach this goal, the use of flow chemistry is quite appealing, allowing a safe operation, an excellent reproducibility and an efficient process
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